Abstract

Diabetes is one of the major risk factors for dementia. However, the molecular mechanism underlying the risk of diabetes for
dementia is largely unknown. Recent studies revealed that epigenetic modifications may play a role in the pathogenesis of
diabetes. We hypothesized that diabetes may cause epigenetic changes in the brain that may adversely affect synaptic function.
We found significant elevation in the expression of histone deacetylases (HDACs) class IIa in the brains of diabetic subjects
compared with control subjects, and these changes coincide with altered expression of synaptic proteins. In a mouse model
of diet-induced type 2 diabetes (T2D), we found that, similar to humans, T2D mice also showed increased expression of HDAC
IIa in the brain, and these alterations were associated with increased susceptibility to oligomeric Aβ-induced synaptic impairments
in the hippocampal formation and eventually led to synaptic dysfunction. Pharmacological inhibition of HDAC IIa restored synaptic
plasticity. Our study demonstrates that diabetes may induce epigenetic modifications affecting neuropathological mechanisms
in the brain leading to increased susceptibility to insults associated with neurodegenerative or vascular impairments. Our
study provides, for the first time, an epigenetic explanation for the increased risk of diabetic patients developing dementia.